C h ro n i c L e u k e m i a

Edythe M. (Lyn) Greenberg,

Alexandra Probst, MS, PA-C

PhD, RN, FNP-BC*,

KEYWORDS
 Chronic myeloid leukemia  Chronic lymphocytic leukemia  Leukocytosis
 Lymphocytosis  Tyrosine kinase inhibitors  Alkylating agents
 Monoclonal antibodies  Immunomodulatory agents
KEY POINTS
 Chronic myeloid leukemia is a myeloproliferative hematopoietic stem-cell disorder of
mature white blood cells of myeloid lineage.
 Chronic lymphocytic leukemia is a monoclonal B-cell disorder.
 Chronic myeloid leukemia is treated with the tyrosine kinase inhibitors.
 Front-line treatment of chronic lymphocytic leukemia includes alkylating agents, purine
analogues, monoclonal antibodies, and immunomodulatory medications.

INTRODUCTION

Approximately 1 in 74 men and women will be diagnosed with leukemia during

their lifetime, with chronic leukemias accounting for 45% of new leukemia cases.1
Typically, chronic leukemias are not immediately life threatening and are classified
by a clonal overproduction of mature white blood cells (WBCs). Chronic leukemias
can be divided into 2 subsets: chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL).
CHRONIC MYELOID LEUKEMIA

CML is a clonal myeloproliferative hematopoietic stem-cell disorder accounting for

approximately 15% of all adult leukemias.2 The median age at diagnosis is 64 years
of age, with a slight male predominance.3 Unique to CML, the Philadelphia chromosome consists of a reciprocal translocation between the ABL gene found on chromosome 9 and the BCR gene from chromosome 22.2 This fusion oncogene results in
BCR-ABL tyrosine kinases and activation of downstream pathways, giving rise to
clonal expansion of Philadelphia-positive cells.2,3 BCR-ABL provides a survival

There is not direct financial interest with any company.

Department of Leukemia, MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston,
TX 77030, USA
* Corresponding author.
E-mail address: emgreenb@mdanderson.org
Crit Care Nurs Clin N Am 25 (2013) 459470
http://dx.doi.org/10.1016/j.ccell.2013.09.003
ccnursing.theclinics.com
0899-5885/13/$ see front matter 2013 Elsevier Inc. All rights reserved.

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(Lyn) Greenberg & Probst

advantage to CML cells by promoting proliferation and suppressing apoptosis.4

Malignant cells accumulate and produce the characteristic features of CML.
Clinical Presentation and Diagnostic Workup

In many cases, CML patients are asymptomatic at the time of presentation, with
abnormalities identified on routine laboratory tests. Some patients present with
nonspecific symptoms including fevers, night sweats, weight loss, and bone pain.
Splenomegaly can be found in 30% to 70% of CML patients at the time of diagnosis.5
Laboratory abnormalities can include leukocytosis, basophilia, eosinophilia, and high
platelet count. An elevated WBC count, usually exceeding 25  109/L, with left shift is
the most common feature of the disease.5
Once a suspicion of CML is established, a bone marrow examination with cytogenetic and molecular testing is mandatory to confirm the diagnosis and identify the disease phase. The bone marrow is typically hypercellular with a predominance of
myeloid precursors.5 Up to 40% of patients can have some degree of myelofibrosis.2
Cytogenetic analysis will identify the presence of the Philadelphia chromosome, validating the diagnosis of CML. Once CML is established, determining the disease phase
is an important factor when considering prognosis and treatment options. Ninety
percent of CML patients are diagnosed in chronic phase, with some patients presenting in more advanced stages to include accelerated or blast phase.2 The University of
Texas M.D. Anderson Cancer Center criteria for these phases are listed in Table 1.
Only 1 criterion in the accelerated or blast phase has to be met to classify the disease
in one of these more advanced stages.
For patients diagnosed in chronic phase, the median survival is approximately 4 to
5 years without tyrosine kinase inhibitor (TKI) therapy.6 Accelerated phase is a transitional phase characterized by a decrease in maturation and a median survival of 1 to
2 years.2 Blast-phase CML is the last and most aggressive stage of the disease,
resembling an acute leukemia. The blasts can phenotypically be myeloid, lymphoid,
or undifferentiated.2 The median survival is 3 to 6 months, with lymphoid blastphase CML patients having a slightly better prognosis than those in myeloid blast
phase.2 As the disease progresses, patients become more symptomatic, with
increased anemia, thrombocytopenia, constitutional symptoms, and risk of
infections.2

Table 1
CML phases
Blasts D
Blasts Promyelocytes Basophils
(%)
(%)
(%)
Platelets
Chronic
Phase

<30

<20

>100,000

No clonal
evolution

Not present

Accelerated 1529 30

Phase

20

<100,000
Clonal
evolution
Unrelated
to therapy

Not present

Present

Blast
Phase

014

Extramedullary
Cytogenetics Disease

30

With or
without
clonal
evolution

Data from Kantarjian HM, Wolff RA, Koller CA. MD Anderson manual of medical oncology. New
York: McGraw-Hill; 2006. p. 174.

Chronic Leukemia

Treatment

While awaiting confirmation of the presence of the Philadelphia chromosome,

hydroxyurea can be initiated for temporary control of elevated WBC counts. Once
the diagnosis of CML is confirmed, TKI therapy is the mainstay of treatment. TKIs specifically inhibit the tyrosine kinase activity of the BCR-ABL oncogene and ABL kinase,
which promotes apoptosis and cell death.7 Imatinib (Gleevec) was the first TKI
medication to be approved by the Food and Drug Administration, in May 2001. For
therapy-nave patients who were diagnosed in chronic phase and treated with imatinib, 83% achieved a complete cytogenetic remission with an overall 8-year survival
rate of 85% and an 81% event-free survival.5 Imatinib is overall a well-tolerated medication, with the most common Grade-1 to -2 adverse events including nausea, edema,
muscle cramps, diarrhea, rash, weight gain, and fatigue.8 Myelosuppression, specifically neutropenia, is the most common Grade-3 to -4 adverse event.8 Table 2
includes a definition of the 5 grades of adverse events.9
Nilotinib, dasatinib, and bosutinib are second-generation TKIs approved for the
treatment of CML. Nilotinib and dasatinib are approved for front-line therapy for
CML patients, while nilotinib, dasatinib, and bosutinib are approved for CML patients
who have previously experienced imatinib resistance or intolerance. In newly diagnosed chronic-phase CML patients, dasatinib and nilotinib have been shown to be
more potent, and with better responses and outcomes than imatinib.10,11 The rate
of complete cytogenetic remission after 36 months of therapy was 58% for imatinib,
compared with 76% for nilotinib and 78% for dasatinib.12 Each second-generation
TKI is overall well tolerated, with a slightly different side-effect profile. Some of the
more common adverse events noted with dasatinib include myelosuppression, pleural
effusions, and headaches.13 Nilotinib has the potential for myelosuppression along
with rash, elevated liver enzymes, and hyperglycemia.14 Bosutinibs side-effect profile
includes diarrhea, nausea/vomiting, and potential elevation of liver enzymes.15
Ponatinib is a potent third-generation TKI currently approved for CML patients who
have been resistant or intolerant to prior TKI therapy. In a recent study, in which
greater than 94% of participants had been intolerant or resistant to at least 2 prior
TKIs, 72% of chronic-phase CML patients had a major cytogenetic response, with
63% of chronic-phase CML patients achieving a cytogenetic remission.16 Ponatinib

Table 2
Grades of adverse events in CML
Grade

Severity

Description

Mild

Asymptomatic or mild symptoms. Clinical or diagnostic

observations only. Intervention not indicated

Moderate

Minimal, local, or noninvasive intervention indicated. Limiting

age-appropriate instrumental activities of daily living (ADL)

Severe

Medically significant but not immediately life-threatening

Hospitalization or prolongation of hospitalization indicated.
Disabling or limiting self-care ADL

Life-threatening

Urgent intervention indicated, otherwise immediately lifethreatening

Death

Death related to adverse event

Data from Kantarjian H, Shah N, Cortes J, et al. Dasatinib or imatinib in newly diagnosed chronicphase chronic myeloid leukemia: 2-year follow-up from a randomized phase 3 trial (DASISION).
Blood 2012;119:11239.

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was also shown to be effective in CML patients who develop the T315i BCR-ABL
kinase mutation, which is highly resistant to all other commercially available TKIs.16
Once TKI therapy has been initiated, routine laboratory tests and follow-up are
necessary to monitor for response and adverse events. A repeat bone marrow examination with cytogenetic and molecular testing is typically performed every 3 to 6 months
for the first 12 months or until a cytogenetic remission has been achieved.17 Diseaseresponse definitions and monitoring guidelines, as per the European LeukemiaNet,
are given in Table 3.18 A suboptimal response is defined as failing to achieve a major
cytogenetic response within 6 months of therapy, or failure to achieve a cytogenetic
remission within 12 months of therapy. A suboptimal response or loss of response to
treatment would be an indication to consider switching to an alternative TKI.
In summary, CML is a chronic leukemia characterized by the Philadelphia chromosome, resulting in clonal myeloproliferation. Most patients are asymptomatic at the
time of diagnosis, and will require a bone marrow evaluation to confirm the presence
of the Philadelphia chromosome as well as to identify the disease phase. For the
90% of CML patients diagnosed in chronic phase, the standard treatment is TKI therapy. Most CML patients respond well to TKIs and go on to live full productive lives
despite their diagnosis of leukemia.
CHRONIC LYMPHOCYTIC LEUKEMIA

CLL, like CML, is a disease of mature WBCs. CLL is an indolent, monoclonal disorder
associated with the progressive accumulation of functionally incompetent mature Bcell lymphocytes.19 CLL constitutes approximately 20% of all leukemias in the United
States, and is the most common leukemia in Western societies.20,21 In the United
States, Asian-Pacific Islanders and Blacks have a much lower incidence of CLL
than Whites.22 CLL also has a low incidence in Asian societies, such as Japan, Korea,
and China.19 CLL increases in incidence with age, with the majority of patients being
older than 50 years at the time of diagnosis.20 Two times more males than females are
diagnosed with CLL. There are no environmental factors, such as ionizing radiation or
toxic chemical exposure, which predispose an individual to CLL. It is suspected that
CLL can be linked to genetic factors. Approximately 20% of individuals with CLL may
have a family member with CLL or another lymphoid cancer.19,21

Table 3
Response definitions and monitoring guidelines for CML
Hematologic Response
Definition

Cytogenetic Response

Complete: WBC <10  109/L, Complete: 0%

Ph1 cells
platelets <450  109/L,
Major: 1%35%
<5% basophils and
Ph1 cells
absence of immature
Minor: 36%65%
granulocytes,
Ph1 cells
nonpalpable spleen

Monitoring Every 2 wk until

complete response
achieved, then
every 3 mo

Molecular Response
Major: BCR-ABL <0.1%
(as per the
International Scale)
Complete: undetectable
BCR-ABL

Every 3 mo
Every 36 mo until
cytogenetic remission
achieved and then
every 612 mo

Abbreviations: Ph1, Philadelphia chromosome positive; WBC, white blood cells.

Data from Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of
chronic myeloid leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2006;108:180920.

Chronic Leukemia

Other diseases, such as hairy cell leukemia, mantle cell lymphoma, marginal zone
lymphoma, and follicular lymphoma, often can masquerade as CLL.23 A similar monoclonal B-cell neoplasm is small lymphocytic leukemia (SLL), an indolent non-Hodgkin
lymphoma. SLL involves the lymph nodes and/or spleen, but has fewer than 5000 K/mL
circulating lymphocytes in the peripheral blood.23,24 Monoclonal B-cell lymphocytosis
(MBL) has an elevated clonal B-lymphocyte count in the peripheral blood, but no
lymphadenopathy, organomegaly, cytopenias, or clinical symptoms.2325 MBL may
be a precursor to CLL.25
Clinical Presentation and Diagnostic Workup

The diagnosis of CLL is a clinical diagnosis. Individuals with CLL can present with
indolent disease or fulminant disease. Early disease may be identified when the
WBC count is elevated (leukocytosis), and the absolute lymphocyte count is greater
than or equal to 5,000 mL (lymphocytosis). The individual may be asymptomatic for
years before a routine complete blood cell count with differential identifies the leukocytosis and lymphocytosis. In the review of systems, the individual may identify B
symptoms, which include unintentional weight loss, fever, drenching night sweats
without evidence of infection, and extreme fatigue. These individuals may have an
exaggerated response to insect stings and bites. Depending on the stage of the
CLL, the individual can also present with splenomegaly, hepatomegaly, skin lesions,
and lymphadenopathy.19
A workup for CLL will include peripheral blood for a complete blood cell count and
differential; a comprehensive metabolic panel; immunoglobulins; direct antiglobulin
test (DAT); testing for human immunodeficiency virus, hepatitis B, and hepatitis C;
and a b2-microglobulin. In addition to an elevated lymphocyte count, the lactate dehydrogenase and b2-microglobulin may be elevated. Usually all of the immunoglobulins (IgG, IgM, IgA) are low (hypogammaglobulinemia), especially in advanced
disease.19,20 A chest radiograph may be included in the workup to evaluate for lymphadenopathy and infection. The physical examination includes measurements of the
superficial lymph nodes (cervical, supraclavicular, infraclavicular, axillary, and
inguinal), spleen, and liver.19 Counseling men and women on fertility options and
the possible effects of treatment on their fertility is also recommended.
A bone marrow aspiration and biopsy is not necessary to make the diagnosis of
CLL, but may identify factors that influence cytopenias.20,23 It is recommended to
perform a bone marrow aspiration and biopsy before initiating treatment, and to
reevaluate the bone marrow if cytopenias persist after treatment.23 The bone marrow
can have 1 of 3 patterns: nodular, interstitial, or a diffuse pattern, which is seen in
advanced disease. With a diffuse pattern the majority of bone marrow is replaced
with hematopoietic cells and fat cells, and indicates advanced disease.19 On the
bone marrow aspiration, at least 30% of the cells should be lymphocytes to confirm
the diagnosis of CLL.23
A CLL panel, fluorescent in situ hybridization (FISH), and conventional cytogenetics
are obtained on the bone marrow or peripheral blood. In CLL, the monoclonal B cells
express the CD5 cell marker commonly found on T lymphocytes.20,23 CLL cells are
also identified by B-cell surface markers including CD19, CD20, and CD23. The surface immunoglobulins, CD20 and CD79b, are expressed in lower levels than are
normal B cells. Each clone of B cells expresses either k- or l-immunoglobulin light
chains.23
Morphologically, the lymphocytes are small and mature with a narrow border of
cytoplasm.23 Smudge cells or cellular debris are identified when fragile lymphocytes
are spread onto a slide.1921 The leukemic lymphocytes may occasionally be mixed

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with large, atypical lymphocytes known as prolymphocytes. More than 55% prolymphocytes in the blood confirms a diagnosis of prolymphocytic leukemia.20,23
Conventional cytogenetics can detect abnormalities in approximately 56% of individuals with CLL.26 Conventional cytogenetic techniques grow CLL cells in a culture and
require prompting of the cells to divide with B-cell mitogens. FISH identifies chromosomal abnormalities on dividing cells, and can identify up to 80% of molecular abnormalities.20 The most common cytogenetic pattern with the most favorable prognosis is the
deletion found on the long arm of chromosome 13. Trisomy 12 and a rare cytogenetic
abnormality on the long arm of chromosome 6 have intermediate risk features.26
The high-risk cytogenetic abnormalities include deletions on the long arm of chromosome 11 and the short arm of chromosome 17. The tumor-suppressor protein
53 (tp53) is located on the short arm of chromosome 17. The tp53 gene is more
commonly identified in individuals with progressive and refractory disease. The ataxia
telangiectasia mutated (ATM) gene may be located on chromosome 11q. Deletions
17p and 11q are associated with a more aggressive disease, poor overall survival
rate, and resistance to traditional chemotherapeutic treatments.26
CLL Staging

CLL can be staged in one of two ways, the Rai staging system and the Binet staging
system. The criteria for the Rai staging system are listed in Table 4 and those of
the Binet system in Table 5. The two staging methods have several disadvantages.
Both methods evaluate the individual only at a single point in time, do not predict
who will have disease progression, and do not determine which individuals will
respond to treatment.21,23,26
Other Prognostic Indicators

Other clinical prognostic indicators are available to determine individuals at high risk
for disease progression, a shorter time to treatment, and poorer prognosis. These
indicators include a short lymphocyte doubling time, a positive Zeta alpha protein
(ZAP-70), positive CD38, somatic mutation in the immunoglobulin heavy-chain variable region genes (IgVH), an increased b2-microglobulin level, diffuse pattern of
bone marrow infiltration, advanced age, and an increased number of prolymphocytes.
A short lymphocyte doubling time is defined as the amount of time it takes for the
lymphocyte count to double. A rapid doubling time within 12 months is associated

Table 4
Rai staging of CLL
Rai Stage

Modified Rai Staging

Criteria

Low risk

Elevated lymphocyte count 5  109

Intermediate risk

Elevated lymphocyte count 5  109

Enlarged lymph nodes

Intermediate risk

Elevated lymphocyte count 5  109

Enlarged spleen or liver with or without
enlarged lymph nodes

High risk

Elevated lymphocyte count 5  109

and hemoglobin <11 g/dL

High risk

Elevated lymphocyte count 5  109

and platelet count <100  109/L

Data from Refs.21,24,25

Chronic Leukemia

Table 5
Binet staging of CLL
Binet Staging

Risk

Criteria

Low

Up to 2 areas of enlarged lymph nodes >1 cm in diameter

Platelets >100  109/L
Hemoglobin 10 g/dL

Intermediate

3 areas of enlarged lymph nodes >1 cm in diameter

Platelets >100  109/L
Hemoglobin 10 g/dL

High

Any number of enlarged lymph nodes >1 cm in diameter

Platelets <100  109/L
Hemoglobin <10 g/dL

Areas of lymph node involvement:

1. Head and neck, including Waldeyer ring
2. Axillae
3. Groin
4. Palpable spleen
5. Palpable liver
Data from Desai S, Pinilla-Ibarz J. Front-line therapy for chronic lymphocytic leukemia. Cancer Control 2012;19:2636; and Sagatys EM, Zhang L. Clinical and laboratory prognostic indicators in
chronic lymphocytic leukemia. Cancer Control 2012;19:1825.

with a shorter mean survival time.23,26 These clinical prognostic indicators can help
identify a CLL patient who is at high risk for disease progression and who may need
early treatment.
Flow cytometry calculates ZAP-70 and the cell surface glycoprotein, CD38. ZAP70
signals T cells, but is abnormally expressed on malignant B cells. ZAP-70 is considered positive when more than 20% of the B cells express ZAP-70 in their cytoplasm.
CD38 is considered positive when more than 30% of the B cells demonstrate CD38 in
their cytoplasm. Individuals with a positive ZAP-70 and CD38 have a poorer overall
survival rate.23,26
Leukemic cells express immunoglobulin, which may have a somatic mutation in the
IgVH. The IgVH is defined as greater than a 2% deviation from the germline nucleotide
sequence. An IgVH value greater than or equal to 2% deviation from the germline
sequence indicates mutation. Individuals with a mutated IgVH have a better survival
rate.26
b2-Microglobulin is a component of the human leukocyte antigen (HLA) class 1 molecules, which are located on all nucleated cells with the exception of red blood cells. A
b2-microglobulin level of less than 3.5 mg/L typically indicates a greater length of time
to progression of CLL. A higher b2-microglobulin level is associated with lower rates of
complete remission and a shorter overall survival rate. Because b2-microglobulin can
also increase with renal disease, an adjustment in the b2-microglobulin level should be
made based on the glomerular filtration rate.26
Thymidine kinase (TK) is a protein involved in DNA synthesis. An increase in TK of
greater than 7.0 U/L in an individual with early CLL can indicate a potential for more
aggressive disease.26
Complications of CLL

Individuals with CLL have a defect in their immune systems that can result in
an increased incidence of autoimmune hemolytic anemia, autoimmune thrombocytopenia, and infections. Autoimmune hemolytic anemia in CLL may present with a

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positive direct antiglobulin (Coombs) test (DAT), a decrease in hemoglobin, an

increased reticulocyte count, elevated indirect bilirubin, or elevated lactate dehydrogenase (LDH).27,28 When the bone marrow is heavily infiltrated with CLL, the DAT
can be negative despite hemolysis, and there may not be an increase in the reticulocyte count. The LDH may also be elevated from disease progression, changes in the
CLL, and liver dysfunction.27 The serum bilirubin may not increase if the liver is able to
metabolize the bilirubin.27 Moreover, the haptoglobulin level will be low.27,28
In autoimmune thrombocytopenia associated with CLL, there is a rapid decrease in
the platelet count. The bone marrow produces an adequate amount of megakaryocytes, but the peripheral blood platelet count remains low. The platelet count is usually
less than or equal to 50,000/mL.28 Front-line treatment includes steroids or intravenous
immunoglobulin (IVIG), followed by rituximab in refractory disease.28
Patients with CLL are immunosuppressed, and therefore should be monitored for
opportunistic infections such as fungal infections (ie, Pneumocystis carinii pneumonia
and Aspergillus pneumonia); bacterial infections (ie, Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae); and viral infections (ie, herpes zoster). CLL patients respond well to antibiotics.19,28 Many CLL patients will develop a
hypogammaglobulinemia during their illness. Low levels of immunoglobulin G are
associated with an increased incidence of bacterial infections such as Streptococcus
pneumoniae and Haemophilus influenzae. Prophylactic IVIG may be beneficial when
levels of immunoglobulin G are low.19,28
Patients with CLL may also develop secondary malignancies such as squamous cell
carcinoma, melanomas, colon cancer, lung cancer, and therapy-related acute myeloid
leukemia/myelodysplastic syndrome.19 CLL can also transform into an aggressive
large B-cell lymphoma known as Richter transformation.19
Front-Line Treatment of CLL

The decision to initiate treatment is determined by the clinical presentation of the individual. Early stage disease (Rai stage 01 or Binet A) in asymptomatic individuals
can be managed with observation and monitoring blood counts until the disease progresses.21 Individuals with intermediate-risk or high-risk disease (Rai stage 24 or
Binet B and C) may benefit from treatment. Active disease should be documented
before initiating treatment. Active disease includes evidence of bone marrow progression; symptomatic splenomegaly or a spleen measuring at least 6 cm below the costal
margin; large lymph nodes; a short lymphocyte doubling time; autoimmune hemolytic
anemia or thrombocytopenia; symptomatic anemia and/or thrombocytopenia; and
B symptoms, including significant fatigue, fevers for 2 or more weeks without any
evidence of infection, or drenching night sweats for at least 1 month or recurrent
infections.20,21,23
If treatment is indicated, chemotherapy options include purine analogues (fludarabine, pentostatin, cladribine), alkylating agents (chlorambucil, bendamustine, cyclophosphamide), monoclonal antibodies (rituximab, ofatumumab, alemtuzumab), or a
combination of these agents.20 Alkylator-based therapy, chlorambucil, was the first
medication used in the treatment of CLL.20,21 Single-agent chlorambucil or when
used in combination with corticosteroids was not proved to increase survival rate.20
With the introduction of newer therapies, chlorambucil has limited uses but may be
effective in the older adult with a poor performance status, because it has fewer
adverse side effects, is rapidly absorbed from the gastrointestinal tract, and is
inexpensive.21
In the 1990s, fludarabine was proved to improve the overall survival of CLL patients
in comparison with chlorambucil. Fludarabine combined with cyclophosphamide has

Chronic Leukemia

demonstrated better complete response rates and a longer duration of remission.20,28

Individuals who were not refractory to fludarabine had a better overall response rate
(80%) when compared with individuals who were refractory to fludarabine (38%).29
With the discovery of monoclonal antibodies, the combination of fludarabine, cyclophosphamide, and rituximab (FCR) became front-line treatment for CLL. Rituximab, a
monoclonal antibody, affects CD20, which can be identified in mature B-cell malignancies, and improves response rates in CLL when given in high doses, frequently,
or administered early in the disease.21,30 Rituximab may sensitize CLL cells to fludarabine. In 1999, investigators from M.D. Anderson Cancer Center treated 300 individuals with FCR.30 At 6 years, the overall survival rate was 77%.31 However, in older
adults (65 years), the FCR regimen may be too toxic because of myelosuppression
and infection. Tolerance to FCR may be dependent on physiologic fitness rather than
chronologic age. In older adults, FCR may be administered with a reduced dosage or a
fewer number of cycles.30
Pentostatin may be substituted for fludarabine, and when administered with cyclophosphamide and rituximab (PCR) may have a lower toxicity in individuals intolerant to
the FCR regimen. However, PCRs overall response rate is lower than that of FCR.30
Bendamustine combined with rituximab is also a less toxic alternative to fludarabine,
but has a complete remission rate lower than that of FCR.30 Bendamustine has also
shown efficacy in refractory or relapsed CLL patients.20,30
Alemtuzumab is a humanized monoclonal antibody that affects CD52, which is a cell
marker expressed on both B-cell and T-cell lymphocytes. Alemtuzumab is effective in
fludarabine-resistant disease or high-risk disease such as deletion 17p/tp53, and has
been combined with FCR (CFAR) in both front-line treatment and relapsed/refractory
disease.30 Alemtuzumab is myelosuppressive, which can result in opportunistic infections such as reactivation of the cytomegalovirus (CMV), Pneumocystis jiroveci pneumonia, herpes simplex virus, Listeria monocytogenes, and Aspergillus pneumonia.30
Any individual treated with alemtuzumab should receive prophylaxis antibiotics for
CMV and pneumocytic pneumonia.
Ofatumumab, a humanized monoclonal antibody, is currently being investigated as
both front-line therapy and in relapsed/refractory disease. Single-agent rituximab and
ofatumumab are less myelosuppressive.30 Most commonly the monoclonal antibodies are associated with transfusion reactions such as hypotension and chills.
Immunomodulatory medications such as lenalidomide have been used both as
single agents and in combination with monoclonal antibodies to treat CLL. In a
2011 study, participants who included adults 65 years and older received lenalidomide
5 mg, which was titrated up to 25 mg as tolerated.32 Treatment was continued until the
CLL progressed. More than 65% of the participants achieved a response, including
a 10% complete response rate, 5% complete response with residual cytopenias,
7% nodular response, and 43% partial response. The most common adverse event
was neutropenia.32
Lenalidomide has been associated with tumor flare syndrome, rashes, fatigue, myelosuppression, and embolic phenomenon. Tumor flare syndrome is most commonly
seen in patients with large lymph nodes, and occurs when the lymph nodes become
larger before shrinking in size. Individuals treated with lenalidomide are at risk for
embolic phenomenon such as deep vein thrombosis and pulmonary emboli. If myelosuppression occurs, the dosage of the lenalidomide may be reduced.33
At present, allogeneic hematopoietic stem-cell transplantation (SCT) is the only option for a potential cure for chronic lymphocytic leukemia.34 Hematopoietic SCT evaluation is recommended for younger individuals with CLL and high-risk features such
as deletion 17p/tp53 and deletion 11q/ATM.20 Autologous SCT may lead to a good

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response rate, but has a high association with relapse. Allogeneic SCT may produce a
durable remission but is associated with higher toxicities.20 New treatments are being
investigated, including the Bruton tyrosine kinase (BTK) inhibitors, BH-3 mimetics, Syk
inhibitors, inhibitors of phosphatidylinositol-3-kinase, and CD37.20
Response to Treatment

Individuals are considered to be in complete remission when they have an absolute

lymphocyte count of less than 5000; lymph nodes measuring less than 1.5 cm; no
splenomegaly or hepatomegaly; no B symptoms; and no cytopenias as evidenced
by an absolute neutrophil count greater than 1500/mL; platelet count greater than
100,000/mL; and hemoglobin greater than 11.0 g. No minimal residual disease should
be present on flow cytometry. Partial remission is defined by a 50% decrease in the
absolute lymphocyte count; a reduction in lymphadenopathy; a reduction by 50%
of pretreatment liver or spleen size by palpation or computed tomography scan;
and at least 1 of the following: blood counts including an absolute neutrophil count
greater than 1500/mL, platelet count greater than 100,000/mL or a 50% improvement
of baseline, or hemoglobin greater than 11.0 g or a 50% improvement over baseline.
CLL is considered to have progressed when there is enlargement of lymph nodes; new
organomegaly or an increase in the size of the liver or spleen by 50%; a 50% increase
in the absolute lymphocyte count; and cytopenias. In a patient who has obtained a
complete or partial remission, relapsed disease is present if the symptoms of disease
reappear 6 or more months after treatment. Refractory disease is defined as disease
progression or treatment failure within 6 months of the chemoimmunotherapy.23
SUMMARY

The chronic leukemias are diseases of mature WBCs. CML is a myeloproliferative hematopoietic stem-cell disorder of mature WBCs of myeloid lineage, and CLL is a
monoclonal B-cell disorder. Over the last decade, new therapies have been developed
for the treatment of these disorders. With the advent of new therapies, individuals with
chronic leukemia are living much longer and are leading fulfilling lives.
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